| Structural highlights
Disease
[GOPC_HUMAN] Note=A chromosomal aberration involving GOPC is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which has a constitutive receptor tyrosine kinase activity.[1] [CFTR_HUMAN] Defects in CFTR are the cause of cystic fibrosis (CF) [MIM:219700]; also known as mucoviscidosis. CF is the most common genetic disease in the Caucasian population, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. CF is a common generalized disorder of exocrine gland function which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] Defects in CFTR are the cause of congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180]. CBAVD is an important cause of sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens.[48] [49] [50] [51] [:]
Function
[GOPC_HUMAN] Plays a role in intracellular protein trafficking and degradation. May regulate CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels. May also regulate the intracellular trafficking of the ADR1B receptor. May play a role in autophagy. Overexpression results in CFTR intracellular retention and degradation in the lysosomes.[52] [53] [54] [CFTR_HUMAN] Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO1.[55]
Publication Abstract from PubMed
The association of the cystic fibrosis transmembrane regulator (CFTR) with two PDZ-containing molecular scaffolds (CAL and EBP50) plays an important role in CFTR trafficking and membrane maintenance. The CFTR-molecular scaffold interaction is mediated by the association of the C-terminus of the transmembrane regulator with the PDZ domains. Here, we characterize the structure and dynamics of the PDZ of CAL and the complex formed with CFTR employing high-resolution NMR. On the basis of NMR relaxation data, the alpha2 helix as well as the beta2-beta3 loop of CAL PDZ domain undergoes rapid dynamics. Molecular dynamics simulations suggest a concerted motion between the alpha2 helix and the beta1-beta2 and beta2-beta3 loops, elements which define the binding pocket, suggesting that dynamics may play a role in PDZ-ligand specificity. The C-terminus of CFTR binds to CAL with the final four residues (-D(-)(3)-T-R-L(0)) within the canonical PDZ-binding motif, between the beta2 strand and the alpha2 helix. The R(-)(1) and D(-)(3) side chains make a number of contacts with the PDZ domain; many of these interactions differ from those in the CFTR-EBP50 complex, suggesting sites that can be targeted in the development of PDZ-selective inhibitors that may help modulate CFTR function.
Association of the cystic fibrosis transmembrane regulator with CAL: structural features and molecular dynamics.,Piserchio A, Fellows A, Madden DR, Mierke DF Biochemistry. 2005 Dec 13;44(49):16158-66. PMID:16331976[56]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Verlingue C, Kapranov NI, Mercier B, Ginter EK, Petrova NV, Audrezet MP, Ferec C. Complete screening of mutations in the coding sequence of the CFTR gene in a sample of CF patients from Russia: identification of three novel alleles. Hum Mutat. 1995;5(3):205-9. PMID:7541273 doi:http://dx.doi.org/10.1002/humu.1380050304
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- ↑ Petreska L, Plaseska D, Koceva S, Stavljenic-Rukavina A, Efremov GD. A novel mutation in exon 12 (Y569C) of the CFTR gene identified in a patient of Croatian origin. Hum Mutat. 1996;7(4):374-5. PMID:8723693 doi:10.1002/humu.1380070402
- ↑ Bienvenu T, Chertkoff L, Beldjord C, Segal E, Carniglia L, Barreiro C, Kaplan JC. Identification of three novel mutations in the cystic fibrosis transmembrane conductance regulator gene in Argentinian CF patients. Hum Mutat. 1996;7(4):376-7. PMID:8723695 doi:<376::AID-HUMU18>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)7:4<376::AID-HUMU18>3.0.CO;2-#
- ↑ Hughes DJ, Hill AJ, Macek M Jr, Redmond AO, Nevin NC, Graham CA. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996;8(4):340-7. PMID:8956039 doi:<340::AID-HUMU7>3.0.CO;2-B 10.1002/(SICI)1098-1004(1996)8:4<340::AID-HUMU7>3.0.CO;2-B
- ↑ Clavel C, Pennaforte F, Pigeon F, Verlingue C, Birembaut P, Ferec C. Identification of four novel mutations in the cystic fibrosis transmembrane conductance regulator gene: E664X, 2113delA, 306delTAGA, and delta M1140. Hum Mutat. 1997;9(4):368-9. PMID:9101301 doi:<368::AID-HUMU13>3.0.CO;2-0 10.1002/(SICI)1098-1004(1997)9:4<368::AID-HUMU13>3.0.CO;2-0
- ↑ Gouya L, Pascaud O, Munck A, Elion J, Denamur E. Novel mutation (A141D) in exon 4 of the CFTR gene identified in an Algerian patient. Hum Mutat. 1997;10(1):86-7. PMID:9222768 doi:<86::AID-HUMU15>3.0.CO;2-W 10.1002/(SICI)1098-1004(1997)10:1<86::AID-HUMU15>3.0.CO;2-W
- ↑ Casals T, Pacheco P, Barreto C, Gimenez J, Ramos MD, Pereira S, Pinheiro JA, Cobos N, Curvelo A, Vazquez C, Rocha H, Seculi JL, Perez E, Dapena J, Carrilho E, Duarte A, Palacio AM, Nunes V, Lavinha J, Estivill X. Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. Hum Mutat. 1997;10(5):387-92. PMID:9375855 doi:<387::AID-HUMU9>3.0.CO;2-C 10.1002/(SICI)1098-1004(1997)10:5<387::AID-HUMU9>3.0.CO;2-C
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- ↑ Friedman KJ, Leigh MW, Czarnecki P, Feldman GL. Cystic fibrosis transmembrane-conductance regulator mutations among African Americans. Am J Hum Genet. 1998 Jan;62(1):195-6. PMID:9443874 doi:10.1086/301681
- ↑ Onay T, Topaloglu O, Zielenski J, Gokgoz N, Kayserili H, Camcioglu Y, Cokugras H, Akcakaya N, Apak M, Tsui LC, Kirdar B. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998 Feb;102(2):224-30. PMID:9521595
- ↑ Bombieri C, Benetazzo M, Saccomani A, Belpinati F, Gile LS, Luisetti M, Pignatti PF. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet. 1998 Dec;103(6):718-22. PMID:9921909
- ↑ Vankeerberghen A, Wei L, Jaspers M, Cassiman JJ, Nilius B, Cuppens H. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID:9736778
- ↑ Malone G, Haworth A, Schwarz MJ, Cuppens H, Super M. Detection of five novel mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in Pakistani patients with cystic fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C). Hum Mutat. 1998;11(2):152-7. PMID:9482579 doi:<152::AID-HUMU8>3.0.CO;2-L 10.1002/(SICI)1098-1004(1998)11:2<152::AID-HUMU8>3.0.CO;2-L
- ↑ Leoni GB, Pitzalis S, Tonelli R, Cao A. Identification of a novel mutation (S13F) in the CFTR gene in a CF patient of Sardinian origin. Hum Mutat. 1998;11(4):337. PMID:9554753
- ↑ Feldmann D, Sardet A, Cougoureux E, Plouvier E, Fontaine JL, Tournier G, Aymard P. Identification of three novel mutations in the CFTR gene, R117P, deltaD192, and 3121-1G-->A in four French patients. Hum Mutat. 1998;Suppl 1:S78-80. PMID:9452048
- ↑ Casals T, Ramos MD, Gimenez J, Nadal M, Nunes V, Estivill X. Paternal origin of a de novo novel CFTR mutation (L1065R) causing cystic fibrosis. Hum Mutat. 1998;Suppl 1:S99-102. PMID:9452054
- ↑ Shackleton S, Harris A. A 2-amino acid insertion mutation (1243insACAAAA) in exon 7 of the CFTR gene. Hum Mutat. 1998;Suppl 1:S156-7. PMID:9452073
- ↑ Picci L, Cameran M, Olante P, Zacchello F, Scarpa M. Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Mutations in brief no. 221. Online. Hum Mutat. 1999;13(2):173. PMID:10094564 doi:<173::AID-HUMU19>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)13:2<173::AID-HUMU19>3.0.CO;2-E
- ↑ Mercier B, Verlingue C, Lissens W, Silber SJ, Novelli G, Bonduelle M, Audrezet MP, Ferec C. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995 Jan;56(1):272-7. PMID:7529962
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- ↑ Zielenski J, Patrizio P, Markiewicz D, Asch RH, Tsui LC. Identification of two mutations (S50Y and 4173delC) in the CFTR gene from patients with congenital bilateral absence of vas deferens (CBAVD). Hum Mutat. 1997;9(2):183-4. PMID:9067761 doi:<183::AID-HUMU13>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1997)9:2<183::AID-HUMU13>3.0.CO;2-Z
- ↑ Bienvenu T, Bousquet S, Vidaud D, Hubert D, Francoual C, Beldjord C, Kaplan JC. A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in a French CBAVD patient. Mutations in brief no. 175. Online. Hum Mutat. 1998;12(3):213-4. PMID:10651488
- ↑ Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. J Biol Chem. 2002 Feb 1;277(5):3520-9. Epub 2001 Nov 13. PMID:11707463 doi:10.1074/jbc.M110177200
- ↑ Cheng J, Wang H, Guggino WB. Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. J Biol Chem. 2004 Jan 16;279(3):1892-8. Epub 2003 Oct 21. PMID:14570915 doi:10.1074/jbc.M308640200
- ↑ He J, Bellini M, Xu J, Castleberry AM, Hall RA. Interaction with cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) inhibits beta1-adrenergic receptor surface expression. J Biol Chem. 2004 Nov 26;279(48):50190-6. Epub 2004 Sep 9. PMID:15358775 doi:10.1074/jbc.M404876200
- ↑ Ousingsawat J, Kongsuphol P, Schreiber R, Kunzelmann K. CFTR and TMEM16A are separate but functionally related Cl- channels. Cell Physiol Biochem. 2011;28(4):715-24. doi: 10.1159/000335765. Epub 2011 Dec, 14. PMID:22178883 doi:10.1159/000335765
- ↑ Piserchio A, Fellows A, Madden DR, Mierke DF. Association of the cystic fibrosis transmembrane regulator with CAL: structural features and molecular dynamics. Biochemistry. 2005 Dec 13;44(49):16158-66. PMID:16331976 doi:10.1021/bi0516475
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